Bone Repair
Osteogenesis continued: osteoblasts and osteoclasts
The production of bone (osteogenesis) continues with the balancing between two processes - the secretion of bone matrix, which is carried out by osteoblasts, and bone erosion, carried out by the macrophage-like osteoclasts. Osteoblasts are found at the surface of existing bone matrix and secrete layers of fresh bone (osteoid) onto it, a process known as aposition. As a result, some osteoblasts continue to be free at the surface, whereas others become "cemented" in their own matrix secretion. Osteoid is then mineralised and hardened by deposition of calcium phosphate crystals - also known as hydroxylapatite - onto it. The osteoblasts which became embedded in the matrix are now known as osteocytes, which continue to secrete small amounts of bone matrix, but are not capapble of dividing.
Interesting Fact! There is evidence that osteocytes may act as mechanosensors. They are the most abundant cells in bone, and despite being "fixed" in the surrounding matrix, they can communicate with each other through processes extended from their plasma membrane.
Maintainance and repair of bone, however, also depends on bone degredation, that is, the demolising of old bone matrix. This happens concurrently with bone formation such that there is a continuous "turnover" of bone formation and degredation. The degredation is carried out by osteoclasts, the precursors of which are monocytes in the bloodstream. They are capable of clinging to the surfaces bone matrix and digesting it, but can also "drill" deeper into bones, leaving tunnels that capillaries can run through, and osteoblasts can line. Osteoclasts are controlled by signals which are secreted from osteoblasts. Macrophage colony stimulating factor (MCSF) and tumour necrosis factor 11 (TNF11), also called RANKL, are two such signals which activate osteoclasts, leading to bone matrix degredation. To prevent excessive degredation, osteoblasts also secrete Osteoprotegerin (OPG) which inhibits RANKL (Figure 3). OPG secretion is augmented by Wnt activation; it is therefore not surprising that higher levels of Wnt activation lead to lower levels of bone matrix degredation. Fracture repair in rodents has been shown to involve the Wnt signalling pathway. Lack of beta-catenin, whose repression is removed when the Wnt pathway is activated, blocks expression of a gene called Osterix and the acquisition of chrondrogenic (cartilaginous) cell fate. In conclusion, it seems that the Wnt pathway can act to regulate the balance between bone matrix deposition and degredation. Disturbance of this balance is the underlying cause of osteoporosis (see
Interesting Fact! If you have ever worn orthodontic braces, you may owe the alignment of your teeth to the Wnt pathway. The steady force applied to teeth remodels the bone tissue around them, and it has been proposed that the mechanical stress activates the Wnt pathway in osteoblasts, regulating the production of RANKL and OPG which regulate osteoclast activity.
Figure 3 - a pre-osteoclasts (i.e. an osteoclasts which has not yet been activated) is activated by the binding of RANKL (Ligand of Receptor Activator of Nuclear Factor kB) to RANK (the receptor). Osteoprotegerin (OPG), however, can also be secreted by osteoblasts when there is greater need for bone formation, and this inhibits the binding of RANKL to its receptor.
Interesting Fact! Leptin - the hormone associated with body weight and appetite regulation, can also act locally to stimulate osteoblasts to form new bone. It can also act through the central nervous system (the brain and spinal cord) to decrease osteoblast activity. It is thought to act through the RANKL/OPG pathway and, in vitro, is has been shown to decrease RANKL mRNA expression but leave OPG expression untouched.
References
Caetano-Lopes J, Canhao H, Fonseca JE: Osteoblasts and Bone Formation. Orgao Oficial De Societdade Portuguesa de Reumatologia - Acta Reumatol Port. 2007:32:103-110
Molecular Biology of the Cell, 5th Edition: Bruce Alberts et al, published by Garland Science 2008, pages 1469-1474.
Fundamentals of Anatomy and Physiology, 7th Edition: Frederic H. Martini, published by Pearson Edcucation, Inc. 2006, pages 180-209.
